Morphological studies have shown that chronic administration of guanethidine to newborn and adult rats specifically and permanently destroys the cell bodies of sympathetic neurons. The objectives of the proposed research program are to determine the permanent biochemical (decreases in catecholamine levels and tyrosine hydroxylase activity in several tissues) and functional (decreases in response to nerve stimulation in the whole animal, isolated perfused vascular beds, isolated nerve-muscle preparations) consequences of guanethidine administration to newborn and adult rats and newborns of other species. These experiments will define a model of sympathectomy with distinct advantages over currently available models (immunosympathectomy and 6-hydroxydopamine sympathectomy) in its completeness of the destruction of the sympathetic innervation of the vasculature and in its unique ability to permanently destroy sympathetic neurons in adult animals. These models of sympathectomy (administration of guanethidine to newborns and adults) will be used to study the role of the sympathetic nervous system in the development and maintenance of genetic, renal, and mineralocorticoid hypertension. The sympathetic nervous systems of genetic hypertensive rats (Okomoto strain) will be destroyed in newborns, young adults, or old (7-8 months) adults by treatment with guanethidine to determine at which stage of the progression of the hypertensive disease ablation of the sympathetic nervous can permanently alter the course of the (essential?) hypertension. Similar experiments will determine the effects of sympathectomy prior to or after the induction and stabilization of renal (silver clip on a renal artery, with and without contralateral nephrectomy) or mineralocorticoid (administration of deoxycorticosterone and saline) hypertensions. In order to determine if the specific cytotoxic effects of guanethidine on sympathetic neurons which are observed in animals also occur in humans, sympathetic ganglia will be examined at autopsy from patients who had taken guanethidine for long periods. It is suggested that the results of these experiments may provide a rationale for the use of guanethidine as a method of chemically sympathectomizing humans in those instances where sympathectomy would be considered as therapy in hypertension or in peripheral vascular disease.